Abstract Zika virus (ZIKV) is a re-emerging mosquito-borne Flavivirus that recently caused an outbreak in the Americas. The establishment of ZIKV transmission cycle in tropical/sub-tropical regions that are endemic to other close-related flaviviruses such as Dengue virus (DENV) has raised concerns, mainly by their cross-immunological interactions and the implications of this for development of severe clinical manifestations. Several groups have demonstrated that DENV-immune serum from humans can enhance ZIKV infection in vitro and in vivo in an immunodeficient mice model. This phenomenon known as Antibody Dependent-Enhancement (ADE) has been linked to severe dengue clinical manifestations. Little is known about the effect of a previous immunity to ZIKV on a subsequent DENV infection. It is highly necessary to characterize correlates of protection in the control of a heterologous secondary DENV or ZIKV infection in the presence of previous DENV or ZIKV immunity in an immunological competent animal model that resemble the human immune system like the Non- Human Primates. Our group have preliminary data showing a potential protective role of the cellular immune response in dengue- immune or ZIKV-immune subjects during a heterologous secondary infection with ZIKV or dengue. The overall hypothesis behind this work is that the cross-primed cellular immune response may be critical controlling the DENV and ZIKV infection and provides heterologous protection against each other. To test this hypothesis, we propose a series of straightforward experiments by depleting the CD4+ or CD8+ or CD20+ cells at different time points before a primary or a secondary infection with dengue or ZIKV. This type of experiment has not been performed before in NHP. For these experiments we will use rhesus macaques bred and housed at the Caribbean Primate Research Center that has proven to be the purer Indian-origin macaque population of all populations in the USA or imported animals, without having a significant level of inbreeding. For first time in any study in the flavivirus field, we will use a large data on the MHC typing of this population to characterize specific CD4 and/or CD8 T cells epitopes playing a role in the T cells immune response against dengue and ZIKV. Understanding correlates of protection between ZIKV and DENV is essential to anticipate the outcome of the secondary infection, the design of diagnostics methods and more relevant, to support the design of highly effective ZIKV and DENV vaccines in the scenario of previous DENV or ZIKV immunity, respectively. Undoubtedly, NHP provide us with a unique immunological tool very close to the human system to provide the answers to the questions we are outlying on this application.